to learn more about the arthur and sonia labatt brain tumour

AcknowledgementWe would like to acknowledge the generous support of the Research Institutes andFoundations of The Hospital for Sick Children and the University Health Network inthe establishment of the Arthur and Sonia Labatt Brain Tumour Research Centre.Special thanks to b.r.a.i.n.child for generously supporting ongoing research projects.

To learn more about the Arthur and Sonia Labatt Brain TumourResearch Centre, log on to our web site at www.sickkids.ca/BTRC/

We can be reached byPhone 416 813-8811Fax 416 813-8456 E-mail [email protected]

2 imagine 04-05

This past year has been characterized by many significant scientific advances in the field

of brain tumour research. We are pleased that some of these have been made within the

Arthur and Sonia Labatt Brain Tumour Research Centre (BTRC). Mouse models which we

(Dr. Guha’s Lab) developed a couple of years ago continue to be advanced and developed.

Dr. McGlade continues to help us in unfolding the mechanisms of tumorigenesis. Dr. Rutka

continues to increase our understanding of medulloblastoma growth and treatment. Dr.

Dirks’ studies on stem cells led to a key publication in Nature in November 2004. Dr. Huang

has furthered our knowledge on the mechanisms controlling the growth of medulloblastoma

and neurolloblastoma. We are also pleased to welcome Dr. Cynthia Hawkins as our new

affiliated scientist in the BTRC.

We are pleased to provide this summary of activities within the Arthur and Sonia Labatt Brain

Tumour Research Centre for the year 2004-2005. We hope our enthusiasm and dedication is

presented to you in a comprehensive fashion in this report.

James T. Rutka MD, PhD, Co-Director

On the front cover (left to right, top to bottom)

Dr. Taylor’s Lab: Andreea Norman, Paul Northcott, Dr. Michael Taylor, Yukiko Nakahara (left to right)

Dr. McGlade’s Lab: Sascha Dho, Cheryl Wolting, Donna Berry, Dan Simoncic, Emily Griffiths,Jenny Nie, Melanie McGill, Kimberly Lau, Christian Smith, Ben Pakuts, Nancy Silva-Gagliardi,Larissa Liontos, Andrea Angus, Dr. Jane McGlade, Sally Benn, Christophe Debonneville (left to right, front to back)

Dr. Rutka’s Lab: James Rutka, Yukiko Nakahara, Mandeep Tamber, Todd Mainprize, Bodour Salhia,Allison Kwan, Stacey Ivanchuk, Soma Mondal, Chinatsu Kasuga (left to right, top to bottom)

Dr. Huang’s Lab: Mei Hua Li, Limei Zhou, Dr. Annie Huang, Daniel Picard, Angela Chan (left to right, top to bottom)

Dr. Guha’s Lab: Amparo Wolf, Sabiha Gardezi, Dr. Ab Guha, Amanda Tong, Qingxia Wei, Joseph Wiley,Johann Micallef, Aaron Gajadhar, Deepak Kamnasaran, Ajay Pandita, Baoping Qian, Zia Karim (left to right, front to back)

Dr. Dirks’ Lab: Sheila Singh, Jen Li, Leanne Jamieson, Dr. Peter Dirks, Ian Clarke, Takuichiro Hide,Erick Ling (left to right, front to back)

Ab Guha MD, MSc, Co-Director

The Annual Scientific Report of the Arthur and Sonia Labatt Brain Tumour Research Centre at The Hospital for Sick Children 3

On September 22, 1997, Arthur and Sonia Labatt donated $5-million to establish the

University of Toronto Brain Tumour Research Centre (BTRC) at The Hospital for Sick

Children (SickKids) and The University Health Network. This gift from the former

President of Trimark Financial Corporation and his wife was the single largest contribution

from a family in the history of The Hospital for Sick Children. The BTRC is a project that

brings together scientists and clinicians studying the problem of human brain tumours

from The Hospital for Sick Children and The University Health Network within the

University of Toronto teaching hospitals system. The BTRC fosters excellence in brain

tumour research, amalgamating the expertise of scientists, clinician-investigators, and

physicians in a virtual laboratory environment at the University of Toronto. A stimulating

research environment has been created allowing scientists to share ideas, resources

and equipment in an atmosphere conducive to achieving excellence in molecular neuro-

oncology research, scientific publications, and translational research.

Currently, the Arthur and Sonia Labatt BTRC is situated on the third floor of the Elizabeth

McMaster Building at The Hospital for Sick Children. Approximately 3500 sq. feet of con-

joined space has been renovated and remodeled to form the physical site. The space is com-

prised of state-of-the-art laboratory bench space fashioned in an “open concept” model. In

2004, two new labs were constructed on the third floor of McMaster adjacent to the Labatt

BTRC, and have been occupied by the lab groups of Dr. Peter Dirks and Dr. Annie Huang.

In August 2005, Dr. Dirks, along with his lab, moved to the Medical and Related Sciences

(MaRS) building at the Toronto General Hospital as an affiliate scientist to the Develop-

mental Biology Program. Dr. Dirks’ relocation has freed up space in the BTRC for Drs.

Michael Taylor and Annie Huang to work together.

About the BTRC logo

The Arthur and Sonia Labatt Brain Tumour Research Centre logo was created at the time

of the Grand Opening of the Centre, January 1999. The logo depicts a dove, symbolizing

hope, carrying a twig in its beak. The twig is actually a piece of double-stranded DNA

representing molecular medicine. Hence, the logo symbolizes the mandate of the BTRC

which is “Hope through molecular medicine.”

Dr. Peter Dirks, Dr. Annie Huang, Dr. Ab Guha, Dr. Jane McGlade, Dr. Michael Taylor, Dr. James Rutka (left to right)

DEVELOPMENT OF THE BTRC

4 imagine 04-05

Dr. James T. Rutka Co-Director Arthur and Sonia Labatt Brain Tumour Research Centre,Principal Investigator

Dr. Rutka’s laboratory has been studying the cytoskeleton as a means to increase our

understanding of the mechanisms by which astrocytoma cells grow, adhere to surrounding

substrates, and invade normal brain tissue. Current studies are aimed at investigating how

cytoskeletal matrix interactions lead to the profound cellular changes we have observed

through a detailed analysis of cell cycle gene alterations, metalloproteinase and inhibitor

secretion, and ultrastructural cytoskeletal relationships.

Recently, we have focused additional research interests on the childhood brain tumour known

as medulloblastoma. We are studying the contributions of the sonic hedgehog (SHH) signalling

pathway in the pathogenesis of medulloblastoma. We have recently shown that an inhibitor

of SHH signalling, Human Suppressor of Fused, is mutated in patients with medulloblastoma.

This gives us a new avenue to pursue treatment of children with this disease.

Dr. Ab Guha Co-Director Arthur and Sonia Labatt Brain Tumour Research Centre,Principal Investigator

Dr. Guha and his colleagues have shown that activated Ras is functionally relevant in human

astrocytomas. Blockade of Ras signalling leads to decreased glioma growth. This activation is

not only found within humangliomas, but also peripheral nerve tumours. Ras and other

signalling pathways are activated by aberrant growth factor receptors in gliomas, such as the

epidermal growth factor receptor (EGFR). Using state-of-the-art technologies, in

collaboration with MDSProteomics, Dr. Guha’s lab is investigating Ras and other signalling

pathways utilized by these receptors to promote growth of gliomas. It is hoped that drugs

being investigated in the Guha lab to inhibit these receptors or their signalling pathways, will

be ultimately efficacious in the clinic.

Another area of interest for the laboratory is the study of angiogenic factors. Brain tumours

remain among the most angiogenic tumours known to man. In particular, vascular endo-

thelial growth factor (VEGF) and Angiopoietins and their receptors are angiogenic specific

and aberrant in human gliomas and peripheral nerve tumours. Dr. Guha’s laboratory is

studying how VEGF and Angiopoietins stimulate and interact to promote angiogenesis, how

they are regulated in normoxia and hypoxic conditions, as well as pharmaceutical inhibition

in pre-clinical models to determine if they are relevant clinical therapeutic targets.

LABORATORY PERSONNEL

Stacey Ivanchuk Graduate Student

Ian Kamaly Resident Research

Chinatsu Kasuga Fellow

Paul Kongkham Graduate Student

Todd Mainprize Graduate Student

Soma Mondal Graduate Student

Amit Ray Fellow

Bodour Salhia Graduate Student

Mandeep Tamber Graduate Student

RESEARCH SUPPORT

b.r.a.i.n.child

Canadian Institutes of Health Research

Katie’s Kids for the Cure

National Cancer Institute of Canada

Ontario Cancer Research Network

Pediatric Brain Tumor Foundation of the United States

LABORATORY PERSONNELAnandh BalasubramaniamPost-Doctoral FellowPriya Bhola Graduate StudentAaron Gajadhar Graduate StudentSabiha Gardezi Co-op StudentDeepak Kamnasaran Post-Doctoral FellowZia Karim Research TechnologistJoydeep Mukherjee Post-Doctoral FellowJohann Micallef Graduate StudentAjay Pandita Research AssociateBaoping Qian TechnicianQingxia Wei Post-Doctoral FellowJoseph Wiley Masters StudentAmparo Wolf Graduate Student

RESEARCH SUPPORTCleveland Clinic FoundationDonald WhitewoodHeart and Stroke Foundation of OntarioNational Cancer Institute of Canada National Institutes of Health Ontario Cancer Research Network


Dr. Jane McGlade Senior Scientist, Principal Investigator

Dr. McGlade’s research is directed towards understanding the molecular changes which

occur during the process of malignant cell transformation. Work in the lab involves several

aspects of signal transduction and the identification and characterization of novel

signalling molecules.

Recently Dr. McGlade has focused specifically on one class of cytoplasmic adapter molecules

and the role they play in the localization, integration and co-ordination of signalling cascade

components within two distinct signalling paradigms. It is hoped that this work will have

broad implications in terms of understanding temporal and spatial organization of mitogenic

signal transduction pathways, as well as the process of asymmetric cell division, and epithelial

cell polarity in mammals.

The long-term goal of this work is to define the molecular processes which regulate the

formation and activation of signalling complexes and how disruption of this regulation can

lead to cell dysfunction and malignant disease.

LABORATORY PERSONNELAndrea Angus Asst Research TechnologistSally Benn Post-Doctoral FellowDonna Berry Research AssociateChristophe Debonneville Post-Doctoral FellowSascha Dho Research AssociateEmily Griffiths Post-Doctoral FellowKimberly Lau Graduate StudentLarissa Liontos Graduate StudentMelanie McGill Graduate StudentJenny Nie Post-Doctoral FellowBen Pakuts TechnicianNancy Silva-Gagliardi Post-Doctoral FellowDan Simoncic Graduate StudentChristian Smith Graduate StudentCheryl Wolting Graduate Student

RESEARCH SUPPORTCanadian Institutes of Health Research The Foundation Fighting Blindness Leukemia Research Fund of Canada National Cancer Institute of Canada

LABORATORY PERSONNELIan Clarke Research AssociatePhedias Diamandis StudentTakuichiro Hide Post-Doctoral FellowLeanne Jamieson Graduate StudentJen Li Technician Erick Ling Masters StudentSheila Singh Graduate StudentRyan Ward PhD Student

RESEARCH SUPPORTCanadian Institutes of Health Research Jack Michael Baker FundJessica Durigon FamilyNational Cancer Institute of CanadaSickKids Research Institute Robert Capotosto Family

Dr. Peter Dirks Scientist, Principal Investigator

The long-term goal of Dr. Peter Dirks’ research program is to determine if a normal neural

stem cell or progenitor cell is transformed into a brain tumour. Two approaches are being

used to study this question. One approach involves a study of primary human brain tumours

to determine if stem cell populations exist in brain tumours.

Our question is: are there a small population of cancer cells in a brain tumour that uniquely

has the ability to maintain the tumour? Dr. Dirks’ lab has recently isolated and characterized

a repopulating cell from human brain tumours of different phenotypes that expresses neural

stem cell markers and has stem cell-like behaviour in vitro. This subpopulation of tumour

cells could be considered as cancer stem cells, because they share properties with normal stem

cells and because they are necessary for maintaining tumour growth in vitro.

The second approach involves a study of the key determinants of proliferation and self-

renewal in normal neural stem cells. We focus on the sonic hedgehog signalling pathway, as

it is perturbed in primary human brain tumours (medulloblastomas), and because it has been

shown to be critically important for normal brain development.

Our preliminary studies suggest that different Shh pathway members play important and

distinct roles in neural stem cell proliferation and self-renewal. A better understanding of how

this pathway functions in normal neural stem cells may help us to better understand brain

tumour proliferation and self-renewal.

6 imagine 04-05

Dr. Annie Huang Scientist, Principal Investigator

Dr. Huang is studying the mechanisms of growth of human neuroblastomas and subtypes of

medulloblastomas using cDNA microarray analyses. Genes that are up-regulated or down-

regulated in these tumours will be further corroborated by RNA and protein analysis. Altered

genes from this analysis will then provide important clues as to the key mechanisms involved in

the growth of neuroblastomas and medulloblastomas.

Dr. Huang’s research focus is in the molecular biology of medulloblastoma, a paediatric cerebellar

tumour. Her studies are directed at identifying biologic/genetic features of medulloblastoma that

correlate with disease outcome, and in delineating the role of poor biologic prognosticators in the

molecular pathogenesis of medulloblastoma.

One of her current studies utilizes the microarray technology to establish genomic and expression

profiles of infant medulloblastoma, a group with particularly poor clinical outcomes. In a related

project she is investigating how c-myc, an oncogene associated with an aggressive variant of

medulloblastoma, interacts with different cellular genes to specify malignant cell transformation.

The long-term goals of these studies are to refine current treatment stratification of children with

medulloblastoma, and to gain insights into novel molecular pathways that may be targeted for

therapy in medulloblastoma.

LABORATORY PERSONNELDaniel Picard Technician 1Mei Hua Li FellowLimei Zhou Research Associate

RESEARCH SUPPORTCanadian Institutes of Health Research Cancer Care OntarioBrain Tumour Foundation of Canada Eli Lilly

Dr. Michael D. Taylor Scientist, Principal Investigator

Dr. Taylor’s laboratory hopes to use the tools of forward and reverse genetics to better understand

the underlying biology of medulloblastoma and ependymoma, two of the most common

malignant paediatric brain tumours.

In forward genetic approaches, the normal cells that are thought to give rise to a cancer are

perturbed in a systemic fashion in an attempt to determine which genes, or signaling pathways

promote malignant transformation. By randomly over-expressing genes in the cellular precursor of

medulloblastoma, we hope to determine which genes are important to the initiation, maintenance,

and progression of medulloblastoma. This sort of functional genomic approach has recently been

made feasible by the completion of the mouse genome project.

In reverse genetics, primary human tumours are studied in an attempt to determine the genetic

events that lead to transformation. The Taylor lab is using a number of genome-wide techniques

to identify novel tumour suppressor genes and oncogenes important in the pathogenesis of

medulloblastoma and ependymoma.

Through an understanding of the genetic basis of brain tumours, it is hoped that novel, rational

therapeutics may be developed that are more effective and less toxic than existing therapies. We

hope that synergism between forward and reverse genetic approaches will allow us to identify key

genes important in brain tumour biology.

LABORATORY PERSONNELYukiko Nakahara Visiting Doctoral FellowAndreea Norman TechnicianPaul Northcott Technician

RESEARCH SUPPORTAmerican Brain Tumor Associationb.r.a.i.n.childCanadian Institutes of Health ResearchLaurie Berman Fund for Brain Tumour ResearchNational Cancer Institute of CanadaSickKids Research Institute

Cynthia Hawkins has been an affiliate scientist at the Arthur and Sonia Labatt Brain Tumour

Research Centre since 2003. Cynthia completed her MD/PhD in 1997 at the University of Western

Ontario. She trained in neuropathology at the University of Toronto including a Post-Doctoral

year in the Department of Neuropathology at the University Hospital in Zurich, Switzerland.

Cynthia was appointed as a neuropathologist at SickKids and assistant professor at the University

of Toronto in 2002 and as a scientist-track investigator at the SickKids Research Institute in 2004.

Cynthia’s laboratory focuses on genetic and proteomic markers for prognostication and therapy

guidance in paediatric brain tumours, in particular medulloblastoma and ependymoma. She also

has active collaborations with Drs. Dirks, Guha, Huang and Rutka.

OUR NEW AFFILIATED SCIENTIST – DR. CYNTHIA HAWKINS


DISTINCTIONS

Peter Dirks Royal College Gold MedalAward in Surgery 2005; George ArmstrongPeters Prize, Department of Surgery,University of Toronto 2005; Promoted toAssociate Professor, Department ofSurgery, 2005; Top 40 under forty 2004

James Rutka Farber Award AmericanAssociation of Neurological Surgeons 2005;Grass Award at the Society of NeurologicalSurgeons Annual Meeting 2004

Ab Guha Indo-Canada Chamber of Com-merce: Humanitarian of The Year 2005

Jane McGlade Award for LeukemiaResearch, Leukemia Research Fund ofCanada 2004; McLaughlin Scholar, R.Samuel McLaughlin Centre for MolecularMedicine 2004

STUDENT AWARDS

Dr. Dirks Sheila Singh The Royal College ofPhysicians and Surgeons of Canada Awardfor Resident Research Andrew Sass-KortsakAward; Stuart Alan Hoffman MemorialPrize; The Warren Ho Memorial Scholarship

Dr. GuhaAaron Gajadhar CIHR Canada GraduateScholarships; Hayden Hantho Award;Restracomp

Deepak Kamnasaran NSERC Scholarship;Alberta Heritage Foundation of MedicalResearch; Heidi Sternbach Scholarship;Javenthey Soobiah Award; Edward ChristieStevens Fellowship

Ajay Pandita Children’s TumorFoundation – Young Investigator

Amparo Wolf MD/PhD CIHR Universityof Toronto Studentship

Joe Wiley James F. Crothers Family Fellow-ship; Restracomp; Frank Fletcher MemorialAward; Dr. Dina Gordon Malkin OntarioGraduate Scholarship in Science andTechnology; Ontario Graduate Scholarship;University of Toronto Vari Scholarship

Dr. McGlade Cheryl Wolting Hunter Studentship, NCICStudentship

Nancy Silva Foundation FightingBlindness – Canada, Research Fellowship

Emily Griffiths NSERC Fellowship, NCICFellowship

Christophe Debonneville Swiss NationalFund for Science Fellowship

Dr. Rutka Bodour Salhia CIHR Fellowship Award

Paul Kongkham b.r.a.i.n.child Award

GRANTS

Dr. Dirks CANADIAN INSTITUTES OF HEALTH RESEARCH Cellular and molecular characterization of cancer stem cells in human brain tumours

NATIONAL CANCER INSTITUTE OF CANADA A study of cancer stem cells in humanbrain tumours

Dr. Guha NATIONAL INSTITUTE OF HEALTH R01: Development of mouse models of humanastrocytomas

CLEVELAND CLINIC FOUNDATION Finding cures for glioblastomas: characterization of a mouse transgenic astrocytoma model as a therapeutic testing platform

NATIONAL CANCER INSTITUTE OF CANADA Development and characterization of transgenic mouse models of astrocytomas

ONTARIO CANCER RESEARCH NETWORK Characterization and identification ofoncogenic receptor protein tyrosine kinase signalling complexes in malignant astrocytomas

NATIONAL CANCER INSTITUTE OF CANADA Role of angiopoietins in human astrocytomas

HEART AND STROKE FOUNDATION OF ONTARIO Neoangiogenesis in cerebral ischemia

Dr. Huang CANCER CARE ONTARIO/ELI LILLY/CANADIAN INSTITUTES OF HEALTH RESEARCH Role of DNA amplification and N-Myc in neuroblastoma

CANCER CARE ONTARIO/ELI LILLY/CANADIAN INSTITUTES OF HEALTH RESEARCH Characterization of a novel family of Myc protein interactors and their role in medullo-blastoma transformation

BRAIN TUMOUR FOUNDATION OF CANADA Identification of markers of chemo-sensitivity in medulloblastoma

Dr. McGlade CANADIAN INSTITUTES OF HEALTH RESEARCH LNX family ubiquitin ligases in cellularsignalling and polarity

LEUKEMIA RESEARCH FUND OF CANADA/THE FOUNDATION FIGHTING BLINDNESS Role of mammalian CRB1 in retinal morphogenesis and degeneration

NATIONAL CANCER INSTITUTE OF CANADA Role of the endocytic adaptor proteinNumb in normal development and cancer

Dr. Rutka ONTARIO CANCER RESEARCH NETWORK Gli2 as a target for the treatment ofmedulloblastoma

NATIONAL CANCER INSTITUTE OF CANADA Role of hedgehog signalling in thepathogenesis of medulloblastoma

CANADIAN INSTITUTES OF HEALTH RESEARCH The role of cytoskeletal GTPases in astrocytoma migration

NATIONAL CANCER INSTITUTE OF CANADA The role of human suppressor offused in medulloblastoma

KATIE’S KIDS FOR THE CURE Sonic hedgehog and WNT signalling blockade as a treatment for paediatric medulloblastoma

CANADIAN INSTITUTES OF HEALTH RESEARCH Cytoskeletal: matrix interactionsregulating astrocytoma tumorigenicity

PEDIATRIC BRAIN TUMOR FOUNDATION OF THE UNITED STATES The role of Gli2 in medulloblastoma

B.R.A.I.N.CHILD VEGF polymorphisms in medulloblastomas

Dr. Taylor UNIVERSITY OF TORONTO Functional genomics of medulloblastoma

UNIVERSITY OF TORONTO Using functional genomic techniques to study the molecularpathogenesis of medulloblastoma

A YEAR IN REVIEW

8 imagine 04-05

2005 BTRC Visiting Lectureship Dr. Darell Bigner

ANNUAL LABATT BTRC ACADEMIC VISITING LECTURESHIP

Previous BTRC Academic Guest Lecturers

1999 Dr. Robert Martuza Professor and Chairman, Department of Neurosurgery, MassachusettsGeneral Hospital, Harvard University

2000 Dr. Gregory Cairncross Professor of Neurology, Director London Regional Cancer Centre,University of Western Ontario

2001 Dr. David Kaplan The Montreal Neurological Institute, McGill University

2002 Dr. Charles Stiles Dana Farber Cancer Institute at Harvard Medical School, Professor,Department of Microbiology and Molecular Genetics

2003 Dr. Luis Parada Southwestern Medical Center at the University of Texas at Dallas

2004 Dr. Eric Holland Associate Professor, Neurosurgery, Neurology & Cell Biology at MemorialSloan-Kettering Cancer Center

Top Row (left to right): Dr. Darell Bigner Guest Speaker; Dr. Ab Guha, Dr. Annie Huang, Dr. James Rutka, Dr. DarellBigner, Dr. Michael Taylor, Dr. Jane McGlade; Dr. Darell Bigner, Jeanne Crispin, from Arthur and Sonia Labatt BrainTumour Research Centre Administration Office

Bottom Row: The meet and greet prior to the Lectureship brought together people from The Hospital for SickChildren and the BTRC

The seventh annual Arthur and Sonia Labatt Brain Tumour Research Centre academic lecturetook place on February 3rd, 2005 at The Hospital for Sick Children.

Guest speaker, Dr. Darell Bigner, is an Edwin L. Jones Jr. and Lucille Finch Jones CancerResearch Professor, Director, Pediatric Brain Tumor Foundation Institute at Duke and Deputy Director, Duke Comprehensive Cancer Center. The topic of Dr. Bigner’s lecture was“Molecularly Targeted Immunotherapy of Brain Tumours.”

Stacey IvanchukIdentification and characterization of novel p14ARF tumour suppressor binding partners

Soma MondalCharacterization of Molecular InteractionsRegulating Glial Development andCytoskeletal Structure

Sheila SinghIdentification of human braintumour initiating cells

Mei Hua Li Fellow CHINA

Chinatsu Kasuga Fellow JAPAN

Yukiko Nakahara Fellow JAPAN


On November 17th, 2004, the Labatt BTRC was visited by Pediatric Brain Tumor Foundation ofthe United States (PBTFUS) President Mike Traynor, Secretary Dianne Traynor, and ExecutiveDirector Aggie Alexander. They spent the day touring the laboratories and learning about all theongoing research projects in the Labatt BTRC.

The PBTFUS is a non-profit organization that seeks to find the cause and cure of brain tumoursin children. Over the years, the PBTFUS has generously provided peer review funds to investigatorsall over North America including Drs. James Rutka and Michael Taylor of the Labatt BTRC.

Left: Mike Traynor, Dianne Traynor and Aggie Alexander in the laboratory of Dr. Rutka

Right: Aggie Alexander, Dianne Traynorand Mike Traynor with Dr. Dirks in thetissue culture facility of the BTRC

THIS YEAR IN THE BTRC

2005 PhD Graduates from the BTRC

Visiting Fellows

Distinguished Visitors from the Pediatric Brain Tumor Foundation of the United States visit the BTRC

10 imagine 04-05

FURTHER GROWTH AND EXPANSION IN THE BTRC

The BTRC boasts a unique collection of investigators with a spectrum of clinical and basic science interest in brain tumour biology.

This forum is an enormous resource and support for clinician-scientists, like myself, who are in the early stages of establishing

our research programs. I was appointed to the BTRC and the Paediatric Brain Tumour Program in the Division of Haematology

Oncology in July 2002. My lab moved to new research facilities at BTRC in February 2005, from our previous location at OCI (the

lab of Dr. Linda Penn). The concurrent re-location of the paediatric brain tumour program clinical offices from SickKids satellite

offices at 180 Dundas St. to the Black Wing, has allowed me to consolidate my clinical and research activities at SickKids. With the

move to new lab facilities at the BTRC, we have been able to expand our research program with the addition of two post-doctoral

fellows, and a summer student trainee to my laboratory. – Annie Huang

The successes of the various BTRC laboratories and personnel led to a requirement for additional space fornew principal investigators and their lab associates. In 2004, work began and was completed with the renova-tion of new laboratory space on the northwest corner of the third floor of the McMaster Building just downthe hall from the main labs of the BTRC. The photographs depict the construction of this state-of-the-art facility in various stages. Currently, the laboratory efforts of Drs. Huang and Taylor are concentrated in thisnew laboratory space.


AFFILIATEDSCIENTISTS

Cameron Ackerley PhD

Sylvain Baruchel MD

David Kaplan PhD

Normand Laperriere MD

Paul Muller MD

James Perry MD

Michael Schwartz MD

Eric Bouffet MD

Jeremy Squire MD

Cynthia Hawkins MD, PhD

Mark Bernstein MD

ADVISORY BOARD OF THE ARTHUR AND SONIA LABATT BRAIN TUMOUR RESEARCHCENTRE

Sonia and Arthur Labatt Benefactors

Dr. Jim Wright Surgeon-in-Chief, SickKids

Dr. Janet Rossant Chief of Research, SickKids Research Institute

Michael O’Mahoney President, SickKids Foundation

Mary-Jo Haddad CEO, SickKids

Dr. Robert S. Bell CEO, University Health Network

Dr. Christopher Paige Director Research, OCI/PMH

Professor Catharine Whiteside Interim Dean, Faculty of Medicine

Helen Berman Benefactor

Dr. David Berman Scientific Advisor

STEM CELLS AND HUMAN BRAIN TUMOURS: DR. DIRKS DISCOVERS THE ROOT OF THE PROBLEM

Following his initial seminal report in Cancer Research September 15, 2003, Dr. Dirks and

his laboratory team published a major study in Nature 432: 396-401, 2004 on the

identification of human brain tumour initiating cells. This body of work has suggested a new

mechanism by which brain tumours grow and form. It further suggests that targeting the

brain tumour stem cell may become an important facet of any new treatment that is proposed

for brain tumours.

In recognition of his ongoing successes as a neurosurgeon and as a scientist, Dr. Dirks was

nominated as one of Canada’s Top 40 Under 40 in April of 2004. He was honoured for

his vision and leadership, innovation and achievement, impact, and development strategy.

In the spring of 2004, Dr. Dirks was promoted to the position of Scientist in the SickKids

Research Institute, and promoted to Associate Professor in the Department of Surgery at

the University of Toronto.

12 imagine 04-05

MAJOR GIFTS

•LAURIE BERMAN FUND FOR BRAIN TUMOUR RESEARCH established in 2002 by

Helen and Joe Berman in memory of their son Laurie. This fund provides ongoing support

for graduate students, post-doctoral research fellows, lab equipment and supplies. The fund

also enables neurosurgical nurses to attend the annual Canadian Congress of Neurological

Sciences meeting.

•THE WILEY FUND IN BRAIN TUMOUR RESEARCH established in 2001 by Averil and Joe Wiley

in honour of their son Andrew who was cared for by Dr. Rutka. This fund supports the

ongoing research projects of two PhD students, and two post-doctoral research fellows.

•BEQUEST FROM THE ESTATE OF ERIC YOLLES A bequest has been received from the estate of

Eric Yolles to be used for furthering research in the BTRC.

•JACK MICHAEL BAKER FUND Brian and Erin Baker have established a fund to further our

work on cancer stem cells in brain tumours. This donation is in honour of their son Jack

Michael Baker.

•ROCHELLE SHERWOOD FUND for Brain Tumour Research. Judy Stein-Korte and Carl Korte

gave generously to establish a fund to support research in the BTRC in honour of Judy’s sister

Rochelle who was diagnosed with a brain tumour. This endowment fund will be used to

support ongoing research projects on esthesioneuroblastoma, medulloblastoma and primitive

neuroectodermal tumours.

•ANNUAL FUND RAISING EVENTS

6th Annual BUNZL for b.r.a.i.n.child Golf Tournament: Each year, BUNZL Canada organizes

a golf tournament where the proceeds go to support b.r.a.i.n.child through the Rigatoni

for Research Dinner and Auction. This year’s golf tournament raised over $125,000 thanks

to the efforts of Carrie Boss, and BUNZL president, John Howlett. We would like to

acknowledge the following major donors to this golf tournament: Anchor Packaging, Atlas

Paper Bag, McNairn Packaging, Pactiv Canada, Par-Pak Ltd, Reynolds Food Packaging

Canada, SCA Tissue Canada, Scott Paper.

Rigatoni for Research Dinner & Auction, organized by Kathy Douthart, is one of SickKids’

largest third-party events. The fundraising efforts of the Douthart family, close friend Judy

Collaton, the Carlan family and the Wolski family, and the Rigatoni for Research committee

have helped give hope to children living with brain tumours and their families. The 7th

annual dinner this year raised over $200,000 for research at the BTRC.

b.r.a.i.n.child is a group of parents, families and friends who have shared the common

experience of caring for a child with a brain tumour. Formed in 1993, this volunteer

organization provides support and education to other parents and patients as well as public

education on the importance of early detection and the special needs of children with brain

tumours. b.r.a.i.n.child is also a major donor to the BTRC, raising money in the community

for research into the causes, treatment, and cure of brain tumours. Gary Kisiloski was

instrumental in supporting b.r.a.i.n.child’s objective of finding a cure for paediatric brain

tumours by hosting summer festivals and numerous golf tournaments.

Maritimes b.r.a.i.n.child in Halifax, Nova Scotia has once again generously provided ongoing

support for research projects at the BTRC.

Amy’s Shining Star is a fundraising event organized biennially by Tim and Sue Scott in

memory of their daughter Amy. This year’s event in Aurora was held on April 2, 2005 and was

highlighted by a dinner, dance and silent auction, which raised in excess of $25,000 for brain

tumour research.

The Arthur and Sonia Labatt

Brain Tumour Research Centre’s

initiatives are further strengthened by

a community of donors who support

research, education and equipment

needs – making possible a culture of

discovery and care that gives hope to

children and families.

We gratefully acknowledge the

following endowment funds which

provide support in perpetuity for

programs and research initiatives

at the BTRC.


PUBLICATIONS

Dirks Publications

Punnett AS, McCarthy LJ, Dirks PB, Hawkins C, Bouffet E: Patients with primary braintumors as organ donors: Case report and review of the literature. Pediatr Blood Cancer 2004Jul 43(1):73-77

Singh SK, Clarke ID, Hide T, Dirks PB: Cancer stem cells in nervous system tumors. 2004Oncogene 23:2367-7273 (REVIEW)

Dirks PB: Brain tumor stem cells. Biol Blood Marrow Transplant 2005, 101(2 Suppl 2):12-13

Guha Publications

Pandita A, Aldape K, Zadeh G, Guha A, James C: Contrasting in vivo and in vitro fates ofglioblastoma cell subpopulations with amplified EGFR. Genes Chromosomes Cancer 2004 Jan 39(1):29-36

Gutmann DH, James CD, Poyhonen M, Louis D, Ferner R, Guha A, Hariharan S, Viskochil D,Perry A: Molecular analysis of gliomas presenting after age ten in individuals with neurofibro-matosis-1: Molecular analysis of astrocytomas presenting after age 10 in individuals with NF1.Neurology 2003 Nov 25 61(10):1397-1400

Zadeh G, Qian B, Sabha N, Okhowat A, Kontos C, Guha A: Targeting the Tie2/Tek receptor inastrocytomas. Am J Pathol 2004 164:467-476

Kimmelman AC, Qiao R, Narla G, Sanfiz A, Bos P, Banno A, Lau N, Li D, Eng F, Beaven S,Bebzeno S, Liang B, Guha A, Martignettii J, Friedman S, Chan A: Suppression of glioblastomatumorigenicity by the Kruppel-like transcription factor, KLF6. Oncogene 2004 Jun 24 23(29):5077-5083

Perrin R, Guha A: Management of malignant peripheral nerve tumors. Neurosurg Clin N Am2004 Apr 15(2):203-216

Guha A: xPharm Brain Cancer. Bhattacharyya (2004) Ex. Edit: Enna SJ, Bylund DB. Pub,Elsevier Inc, New York: http://editorial.xpharm.com

Watson MA, Perry A, Tihan T, Prayson RA, Guha A, Bridge J, Ferner R, Gutmann DH: Geneexpression profiling reveals unique molecular subtypes of neurofibromatosis type 1-associatedand sporadic malignant peripheral nerve sheath tumors. Brain Pathol 2004 (14):297-303

Meagan’s Walk was created to raise hope, awareness and research funding for children with

brain tumours. It is an outstanding example of the impact of a dedicated group of

individuals. Over the past three years Meagan’s Walk: Creating a Circle of Hope has raised total

funds in excess of $600,000. Meagan’s Walk is a 5 km walk that takes place every year on

Mother’s Day. The walk starts at Ontario Place and ends with a human embrace of SickKids.

The hug reaches out with a strong message of hope to the children and the parents within the

hospital and beyond. Five-year-old Meagan Bebenek died in June 2001 after a six-month

battle with brain stem glioma, a terminal form of brain cancer. Meagan’s story has touched

the hearts of thousands across the country and beyond. Denise Bebenek first envisioned this

hug of the hospital in the months following Meagan’s death. With Meagan as a guide and the

support of her family and friends, the walk and hug became reality. The fourth annual

Meagan’s Walk, on May 8, 2005, involved over 2,000 participants. Special thanks are given to

IKEA North York and IKEA Etobicoke which were the major corporate sponsors of the event.

Thank you to everyone for each contribution. They all help us continueour work for you.

14 imagine 04-05

Zadeh G, Koushman K, Shannon P, Guha A: Interaction of angiopoietins and VEGF in astrocy-tomas. J Neuropath & Expt Neurology 2004 63(9): 978-989

Raut V, Walsh RM, Bath AP, Bance ML, Guha A, Tator CH, Rutka JT: Conservative management of vestibular schwannomas – Second review of a prospective longitudinal study. Clin Otolaryngol2004 Oct, 29(5):505-514

Bhattacharyya A, Perrin R, Guha A: Management of peripheral nerve tumors. Journal of Neuro-Oncology 2004 69:335-349

Mukherjee J, Guha A: Advances in Biology of Astrocytomas. Current Opinion in Neurology.2004 Dec 17(6):655-662

Huang Publications

Hughes S, Lim G, Beheshti B, Bayani J, Marrano P, Huang A, Squire JA: Genome amplification andcomparative genomic hybridisation to detect chromosomal copy number alterations in cell linematerial and tumour tissue. Cytogenet Genome Research 2004 105(1):18-24

Corson TW, Huang A, Tsao MS, Gallie BL: K1F14 is a candidate oncogene in the 1q minimalregion of genomic gain in multiple cancers. Oncogene 2005 14; 24(30):4741-4753

Huang A, Ho CSW, Ponzielli R, Baryste-Lovejoy D, Bouffet E, Picard D, Hawkins CE, Penn LZ:Identification of a novel c-Myc protein interator, JPO2, with transforming activity in medulloblas-toma cells. Cancer Research 2005 1 65(13):5607-5619

Lafay-Cousin L, Holm S, Qaddoumi I, Nicolin G, Bartels U, Tabori U, Huang A, Bouffet E: Weeklyvinblastine in pediatric low grade glioma patients with carboplatin allergic reaction. Cancer 200515 103(12):2636-2642

McGlade Publications

Smith CA, Dho SE, Donaldson J, Tepass U, McGlade CJ: The cell fate determinant numb interactswith EHD/Rme-1 family proteins and has a role in endocytic recycling. Mol Biol Cell 2004 May 21[Epub ahead of print]

Nie J, Li SS, McGlade CJ: A novel PTB-PDZ domain interaction mediates isoform-specific ubiquitylation of mammalian numb. Journal Biol Chem 2004 May 14;79(20):20807-20815.Epub 2004 Feb 27

Zhu YX, Benn S, Li ZH, Wei E, Masih-Khan E, Trieu Y, Bali M, McGlade CJ: Claudio JO andStewart AK: The SH3-SAM adaptor HACS1 is up-regulated in B cell activation signaling cascades.J Exp Med 2004 200(6):737-747

Young P, Nie J, Wang X, McGlade CJ, Rich MM, Feng G: LNX1 is a perisynaptic Schwann cell specific E3 ubiquitin ligase that interacts with ErbB2. Mol Cell Neuroscience 2005

McGill MA and McGlade CJ: “Cellular Signaling” in The Basic Science of Oncology. FourthEdition. Edited by Tannock, Hill, Bristow and Harrington. McGraw-Hill 2005

Rutka Publications

Kuo JS, Rutka JT: Advances in understanding the molecular biology of brain tumors. JournalKorean Neurosurgical Society 2004 35:1-11

Spiegler BJ, Bouffet E, Greenberg ML, Rutka JT, Mabbott DJ: Change in neurocognitive functioningafter treatment with cranial radiation in childhood. Journal of Clinical Oncology 2004 22 (4):706-713

Nolan MA, Sakuta R, Chuang N, Otsubo H, Rutka JT, Snead OC, Hawkins CE, Weiss SK:Dysembryoplastic neuroepithelial tumors in childhood. Neurology 2004 62:2270-2276

Kim DS, Hubbard SL, Peraud A, Salhia B, Sakai K, Rutka JT: Analysis of mammalian septin expres-sion in human malignant brain tumors. Neoplasia 2004 6(2):168-178

Taylor MD, Zhang X, Liu L, Hui C, Mainprize TG, Scherer SW, Wainwright B, Hogg D, Rutka JT:Failure of a medulloblastoma derived mutant of SUFU to suppress WNT signaling. Oncogene 200423:4577-4583


Yokota N, Mainprize TG, Taylor MD, Kohata T, Loreto M, Ueda M, Dura W, Grajkowska W,Kuo JS, Rutka JT: Identification of differentially expressed and developmentally regulated genes inmedulloblastoma using suppression subtraction hybridization. Oncogene 2004 23:3444-3453

Bos JT, Rempel SA, Rutka JT: International hermelin brain tumor symposium on matricellularproteins in normal and cancer cell-matrix interactions. Matrix Biology 2004 23/1:64-70

Rutka JT, Kuo JS, Carter M, Ray A, Ueda S, Mainprize TG: Advances in the treatment of pediatricbrain tumors. Expert Rev Neurother 2004:879-893

Sakai K, Peraud A, Mainprize T, Nakayama J, Tsuga A, Hongo K, Kobayashi S, Rutka JT: Inducibleexpression of p57KIP2 inhibits glioma cell motility and invasion. Journal of Neuro-Oncology 200468(3):217-223

Pietsch T, Taylor MD, Rutka JT: Molecular pathogenesis of childhood brain tumors. Journal ofNeuro-Oncology 2004:1-13

Rutka JT, Kuo JS: Pediatric Surgical Neuro-oncology: Current best care practices and strategies.Journal of Neuro-Oncology 2004 69:139-150

Ray A, Ho M, Ma J, Parkes RK, Mainprize TG, Ueda S, McLaughlin J, Bouffet E, Rutka JT, HawkinsCE: Clinicobiological model predicting survival in medulloblastoma. Clinical Cancer Research2004 10:7613-7620

Ng D, Stavrou T, Liu L, Taylor MD, Gold B, Dean M, Kelly MJ, Dubovsky EC, Vezina G,Nicholson HS, Vyrne J, Rutka JT, Hogg D, Reaman GH, Goldstein AM: Retrospective family studyof childhood medulloblastoma. American Journal of Medicine Genetics 2005 134A(4):399-403

Ivanchuk SM, Rutka JT: The cell cycle: accelerators, brakes, and checkpoints. Neurosurgery 200554(3):692-699

Mabbott DJ, Spiegler BJ, Greenberg ML, Rutka JT, Hyder DJ, Bouffet E: Serial evaluation ofacademic and behavioral outcome following treatment with cranial radiation in childhood. Journalof Clinical Oncology 2005 23-(10):2256-2263

Taylor Publications

Taylor MD, Mainprize TG, Hawkins C: Dysembryoplastic Neuroepithelial Tumor: Textbook ofNeuro-Oncology. (eds) Berger and Prados. Elsevier, 2005:682-686

Taylor MD, Rorke LB: Atypical Teratoid/Rhabdoid Tumors. Textbook of Neuro-Oncology. (eds)Berger and Prados. Elsevier, 2005:744-750

Taylor MD, Bernstein M: Surgical Management of Gliomas. Cancer of the Nervous System. (eds)Schiff and O’Neill

Yokota N, Mainprize TG, Taylor MD, Kohata T, Loreto M, Ueda S, Dura W, Grajkowska W, Kuo JS,Rutka JT: Identification of differentially expressed and developmentally regulated genes in medul-loblastoma using suppression subtraction hybridization. Oncogene 2004 Apr 22 23(19): 3444-3453

Pietsch T, Taylor MD, Rutka JT: Molecular pathogenesis of childhood brain tumors. JournalNeurooncol 2004 Nov 70(2):203-215

Taylor M, Chambers A, Perry J, Bernstein M, and the Neuro-Oncology Disease Site Group:Evidence-based review of the role of surgery for malignant glioma: Current Oncology 2004 11:53-62

Ng D, Stavrou T, Liu L, Taylor MD, Gold AM, Dean M, Dubovsky EC, Vezina G, Nicholson HS,Byrne J, Rutka JT, Hogg D, Reaman GH, Goldstein AM: A retrospective family study of medul-loblastoma. American Journal of Medical Genetics 2005 134(4):399-403

Taylor MD, Poppleton H, Fuller C, Su X, Yongxing L, Jensen P, Magdelano S, Dalton J, Board J,MacDonald T, Rutka JT, Guha A, Gajjar A, Curran T, Gilbertson RJ: Radial Glial Cells areCandidate Stem Cells for Ependymoma. In Press, Cancer Cell 2005

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AcknowledgementWe would like to acknowledge the generous support of the Research Institutes andFoundations of The Hospital for Sick Children and the University Health Network inthe establishment of the Arthur and Sonia Labatt Brain Tumour Research Centre.Special thanks to b.r.a.i.n.child for generously supporting ongoing research projects.

To learn more about the Arthur and Sonia Labatt Brain TumourResearch Centre, log on to our web site at www.sickkids.ca/BTRC/

We can be reached byPhone 416 813-8811Fax 416 813-8456 E-mail [email protected]

to learn more about the arthur and sonia labatt brain tumour

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